The present invention relates generally to methods and apparatus for delivering a substance, e.g. a drug or therapeutic or diagnostic agent, into the wall of a blood vessel or other body duct or vessel from the lumen of the vessel through application of a fine spray or mist of the substance at a high velocity from a plurality of infusion holes distributed around a relatively short infusion segment of an infusion catheter body.
The above-reference parent patent sets forth a discussion of the delivery of thrombolytic agents including plasminogen activators and heparin compounds through various types of catheters to dissolve blood clots or thrombi in native blood vessels and in vascular grafts and dialysis grafts. Such plasminogen activators include streptokinase, urokinase and tissue plasminogen activator (t-PA) and their analogues have been administered as lytic agents for lysis of arterial and venous thromboses. Such thrombolytic agents are delivered within the lumen of native blood vessels and in vascular grafts and dialysis grafts and that discussion is incorporated herein by reference.
Catheters have also been described that are designed to be employed to locally deliver a drug or therapeutic or diagnostic agent intramurally, that is into the wall of a blood vessel or other body duct or vessel, from the lumen of the vessel. Systemic administration of drugs treats the organism as a whole, even though the disease may be localized, such as injury to a body duct or vessel wall. Vessel walls are lined by a smooth lumen surface referred to as the endothelial layer that improves vascular blood flow hemodynamics and shields deeper vessel wall layers from contact with body fluids, e.g., blood in a blood vessel. Localized delivery of a drug intramurally into organ cavity walls, duct walls and blood vessel walls from the organ cavity or duct or vessel lumen poses special problems, since, by nature, the endothelial layers of such walls serve to transport and/or contain fluids within the organ cavity or duct or vessel lumen or transport systems.
Atherosclerotic disease causes localized occlusion of the blood vessels resulting from the build-up of plaque, and certain occlusion clearing treatment procedures and equipment can cause unintended injury to the blood vessel wall. Plaque deposits on an arterial wall effectively reduces the artery diameter and impede blood circulation past the deposits. Percutaneous transluminal coronary angioplasty (PTCA), or simply angioplasty, has proven to be a useful procedure for the treatment of localized atherosclerotic lesions (plaque deposits) of both coronary and peripheral vessels. Angioplasty involves the insertion of catheters, such as balloon catheters, through the occluded region of the blood vessel in order to mechanically expand a lumen through the occluded region by expansion of the balloon. A wide variety of atherectomy devices have also been proposed to open an occlusion and abrade or cut away the plaque deposits.
Unfortunately, successful atherectomy and PTCA invariably involves some interruption of the endothelial lining with a resulting violation of the barrier it provides between the deeper placed intima and smooth muscle cells (SMC) of the vessel wall and the blood itself. Local hemodynamic flow characteristics are also affected. The mechanical abrasion of the intima and the proliferation of smooth muscle cells stimulated by the atherectomy or PTCA procedure is believed to be responsible for restenosis, or closing of the vessel lumen that sometimes occurs. Restenosis may also occur as a result of clot formation due to an atherectomy or PTCA procedure caused injury to the vessel wall which triggers the natural clot-forming reactions of the blood.
It has been proposed that one method of combating restenosis might be the administration of various therapeutic agents known to block intimal and smooth muscle hyperplasia. The typical methods of intravascular medication involve the delivery of the medication systemically, either intravenously, or regionally (e.g., by intracoronary infusion). Systemic delivery is usually ill-suited to the treatment of conditions occurring at one or more discrete sites, because it involves the delivery of the medication to sites other than the target site, and it requires the infusion of large doses of the medication to assure the delivery of a therapeutic dose to the target site, thereby creating the possibility of deleterious effects. Another problem of systemic administration is the inevitable fluctuations of serum drug concentrations that it produces. The dosage that can be delivered to the target site may be limited by the need to minimize unwanted effects in other parts of the body. Furthermore, systemic delivery exposes the medication to possible degradation and elimination by the action of other bodily organs. For these reasons, systemically administered drugs such as anticoagulants, vasodilator, etc. have so far proven ineffective to prevent restenosis. More radical treatment involving agents such as cytostatic drugs or general enzyme blockers may prevent smooth muscle cell proliferation, but often these agents are toxic to humans at the levels necessary to effectively block development of the involved pathology.
Recently, site-specific drug delivery to the arterial wall has become a new strategy for the treatment of vascular diseases, including vessel restenosis following PTCA or atherectomy. These drug delivery systems include: (1) intravascular devices for site-specific (coronary artery) drug delivery comprising double-balloon catheters, porous balloon catheters, microporous balloon catheters, channel balloon catheters, balloon over stent catheters, hydrogel coated balloon catheters, iontophoretic balloon catheters and stent devices; (2) periadventitial and epicardial drug delivery devices, requiring surgical implantation, which include drug-eluting polymer matrices and a iontophoretic patch device; and (3) intramural injection of drug-eluting microparticles. See, for example, the descriptions of such devices appearing in U.S. Pat. Nos. 5,900,433, 5,954,706 and 5,112,305.
Drug delivery catheters of the perforated balloon type are disclosed, for example, in U.S. Pat. Nos. 5,087,244, 5,112,305 and 5,344,402. Catheters of these types have some drawbacks. For example, because the same fluid is used as the balloon inflation medium and as the drug medium, dilatation by balloon expansion is necessarily accompanied by drug delivery; neither function can be performed independently, which may be disadvantageous or inefficient in various clinical situations. Further inefficiency is engendered by the expulsion of the therapeutic agent before the balloon is fully expanded, so that the agent is not as forcefully administered to the luminal wall tissue as it would be if the balloon were fully expanded so as to bring it into close proximity or contact with the wall. A related problem is that the agent is typically expelled at relatively low pressures that are insufficient to effect any substantial degree of penetration of the lumen wall surface, thereby limiting the therapeutic effect of the agent in certain situations. Finally, in drug delivery PTA catheters in which the same fluid is used as the balloon inflation medium and the drug medium, the reversal of fluid flow to deflate the balloon may tend to draw blood into the catheter lumen, requiring it to be withdrawn for purging or replacement after a single use.
Direct injection of drugs from infusion ports of a catheter against the endothelial layer and into the vessel wall have also been proposed in commonly assigned U.S. Pat. No. 5,554,114. A catheter body without a balloon is provided that can be advanced in a straight configuration to the injured or diseased vessel site of and then transformed into a loose, helical distal infusion segment having infusion ports arranged toward the vessel wall.
Thus, problems remain however in the exact method by which the local administration of drugs or therapeutic agents should be accomplished. Conventional methods of drug therapy, as discussed above, often result in blood levels of the cytotoxic agent that are dangerous for the patient. Even with local administration of these agents, one must consider that the normal blood flow of the vessel vill dilute the local concentration of the therapeutic agent by a wash-out effect. The need remains, therefore, to devise a system whereby otherwise toxic therapeutic agents are concentrated and localized intramurally within the affected vessel wall segment.
In addition to the need for improved drug delivery to counter restenosis, there is a more general need in many branches of medicine for improved localized internal delivery of substances including therapeutic agents and drugs and diagnostic agents into the walls of ducts, organs and vessels. In particular, there is need for improved delivery into tissue and into cells themselves within organs, ducts, tracts and vessels of the body via percutaneous and luminal access.
The present invention relates to a number of approaches to satisfying these needs for delivering a substance or lining penetration infusate, e.g., a therapeutic agent or drug or diagnostic agent, intramurally into a localized section of the wall of a body vessel, duct, tract, vein, artery, or organ (herein body vessel).
In one embodiment of the invention, a selected bolus volume of such a substance (referred to herein as a lining penetration infusate) is injected at a selected flow rate into a high strength catheter lumen of an infusion catheter having a distal infusion segment formed in accordance with the present invention. The corresponding bolus volume is ejected or emitted through multiple side wall perforations or infusion holes closely spaced from one another in the relatively short infusion segment as high velocity, low volume, lining penetration jets that penetrate the adjacent endothelial layer. The catheter infusion segment is advanced through the localized section of interest, and the high velocity intramural penetration of the adjacent endothelial layer is repeated as necessary.
The fine, high velocity, lining penetration jets result from the injection of a bolus of lining penetration infusate having a prescribed fluid density at a selected pressure and injection rate of flow (volume per unit of time) into the catheter lumen which is controlled by a power injector. The outflow rate of lining penetration infusate from the infusion holes is proportional to the total number and size (i.e., the total outflow area) of the infusion holes in the infusion segment, the pressure applied to the bolus as it is injected, and other factors. The injected bolus of lining penetration infusate injected into the catheter lumen forces a corresponding fraction of the bolus through each infusion hole. The ejection velocity of the lining penetration jets is related to the outflow rate and inversely proportional to the total outflow area. The outflow rate is selected to maximize the velocity of the high velocity, lining penetration jets of infusate to ensure penetration of the lining penetration infusate into the interior layers of the wall of the body vessel.
The infusion holes are dense in the infusion segment, and the infusion segment is relatively short, between 0.2 cm to 2.0 cm long, to provide a thorough coverage of the section of the endothelial layer of the wall of the body vessel. For example, in one embodiment, 30 to 50 infusion holes are preferably provided per centimeter of length of the infusion segment and are evenly distributed around the circumference of the catheter body in each such cm of length. In another embodiment, the 20 to 32 infusion holes per linear centimeter are distributed in a helical pattern extending around the infusion segment and are closely spaced from one another. The high density spray of high velocity, lining penetration jets causes the section of endothelial lining surrounding or adjacent to the short, 0.2 cm to 2.0 cm long, infusion segment to be thoroughly penetrated.
In use, the lining penetration infusate preferably includes the a radiopaque material that can be observed under fluoroscopy as it is emitted from the infusion holes as fine, high velocity, lining penetration jets. The catheter infusion segment can be advanced back and forth in the section of the endothelial layer by the physician manipulating the proximal portion of the catheter during the emission of the lining penetration jets to distribute the intramurally delivered lining penetration infusate more evenly. The distribution of the radiopaque, lining penetration infusate can be observed under fluoroscopy or other radiographic imaging.
In relatively large body vessels, the distal infusion segment preferably incorporates a biasing mechanism operable from the catheter proximal end in a biasing state for biasing the catheter side wall and at least certain ones of the infusion holes of the infusion segment into close relation with the section of the vessel wall. Exemplary biasing mechanisms include a laterally inflatable asymmetric balloon or a laterally deployable wire or a coiled configuration of the infusion segment.
A number of advantages flow from the present invention. The present invention provides for a rapid intramural injection of lining penetration infusate as high velocity, lining penetration jets. The penetrable distal tip valve allows over-the-wire introduction of the catheter which is simple and allows access to a wide number of locations, e.g. through the abdominal aorta, the iliac, femoral popliteal and tibial blood vessels as well as small diameter cerebral blood vessels. The catheter employed is relatively inexpensive and disposable.